Frailty, Physical Function Impairment and Pulmonary Function in Aging Men with and without HIV from the Multicenter AIDS Cohort Study (MACS)

Background People aging with HIV (PAWH) experience greater impairment in physical and pulmonary function than individuals aging without HIV. We examined whether baseline physical function was associated with subsequent pulmonary impairments. Methods Associations of frailty and physical function (gait speed [m/sec], grip strength [kg]) with pulmonary function (< 80% predicted diffusing capacity for carbon monoxide [DLCO] and forced expiratory volume [FEV1]) 3 years later were modeled; age, HIV status, and smoking were assessed as effect modifiers. Results Among1,024 men, (54% PAWH, 10% frail, 51% pre-frail), mean (SD) age = 53 (12) years, cumulative smoking = 12 (19) pack-years, gait speed = 1.1 (0.2) m/sec, and grip strength = 36.6 (9.2) kg. Frailty, pre-frailty, and weak grip strength were associated with higher odds of subsequent impaired DLCO and FEV1. Slow gait speed was associated with higher odds of DLCO impairment but not FEV1. No statistically significant modifications were found. Conclusion Interventions to improve physical function may help preserve pulmonary function.


Introduction
The life expectancy for people aging with HIV (PAWH) has increased due to effective antiretroviral therapy (ART).In 2019, about half of U.S. adults with HIV were over the age of 50 [1][2][3][4].PAWH are at higher risk of developing adverse health outcomes earlier with greater severity, including frailty and physical function impairments [5][6][7].Frailty and pulmonary disease may co-occur due to shared risk factors and pathophysiological mechanisms [5][6][7][8][9][10][11][12][13][14].Research suggests a bidirectional association between frailty and respiratory impairments [14].We, and others, have shown pulmonary impairment is associated with increased subsequent frailty risk, decreased gait speed, and weaker grip strength, among men with and without HIV [14][15][16][17][18].Here we hypothesize that frailty and physical function impairments (slow gait speed and weak grip strength) are associated with subsequent impaired pulmonary function, and that associations would be greater among PAWH, older adults, and smokers.

Study Population
The MACS, now part of the Multicenter AIDS Cohort Study/Women's Interagency HIV Combined Cohort Study (MACS/WIHS-CCS) [19], began in 1984 and enrolled men with or at risk of HIV at four study centers (Baltimore/Washington DC, Chicago, Pittsburgh/Columbus, and Los Angeles) and three enrollment cohorts (before 1995, between 2001-2009, and 2010 and later).Institutional review board approval was obtained at each site.MACS details have been published elsewhere; in brief, participants completed semi-annual visits for demographic, clinical, and laboratory assessments [20,21].Pulmonary function tests (PFTs) were conducted from 2017-2019.Participants were invited to undergo PFTs; those who consented, completed PFTs and had measurements that passed quality control standards were included here [22,23].The visit three years prior to PFTs was considered baseline for frailty, gait, and grip assessments.If the baseline visit was missing frailty or physical function assessments, then the next visit (up to one year prior to PFTs) was used.Participants who seroconverted during follow-up were excluded (n = 13).Detailed information about PFT testing and exposure measures (frailty, gait speed, grip strength) are included in supplemental material.

Effect Modi ers
Age, HIV serostatus, and cumulative pack-years of smoking (at baseline) were examined as potential effect modi ers on the associations of frailty and physical function with pulmonary function.

Covariates
Baseline HIV serostatus, enrollment center, race (self-reported and categorized into: Black, White, Other), age, cumulative pack-years of smoking and enrollment cohort were included in all models.In models examining interactions of age with DL CO or FEV 1 (using absolute measurement), height (in cm) was also included.Potential baseline confounders included: education level, weight, body mass index (BMI), cardiovascular risk (Framingham coronary heart disease 10-year risk score %), diabetes de ned as hemoglobin A1c ≥ 6.5% or fasting glucose ≥ 126 mg/dL or self-reported diagnosis of diabetes with medication use, use of cholesterol lowering medication, treatment for depression, current or prior con rmed diagnosis of kidney disease, hepatitis C seropositivity, hepatitis B (surface antigen positive or resolved vs negative), and any use since last visit of alcohol, marijuana, cocaine and/or heroin.

Statistical Analysis
Statistical analyses utilized SAS v9.4 (Cary, NC).Logistic regression models determined associations of frailty and physical function with pulmonary function.Interaction terms between each exposure (frailty, gait speed, and grip strength) and age, HIV serostatus, or smoking were explored to determine if they separately modi ed associations between frailty or physical function and pulmonary function (supplemental materials).Exploratory analyses examined if frailty components other than gait speed or grip strength (i.e., weight loss, exhaustion, or low physical activity) were associated with pulmonary function impairment.

Minimal Clinically Important Differences (MCID) for Effect Modi cation
Interaction terms between frailty or physical function with age, HIV serostatus, or smoking were considered separately.A minimal clinically important difference (MCID) was determined based on the literature and/or clinical expertise [23][24][25][26] (supplemental materials).

Results
Of 1,133 men with PFTs, 1,024 and 1,007 met inclusion criteria for DL CO and FEV 1 analyses, respectively.
Overall, 54% and 55% of the DL CO and FEV 1 participants, respectively, were PAWH.Cohort characteristics are reported in Table 1.Sixteen and 14 participants with DL CO and FEV 1 measures, respectively were missing frailty measurement.On average, participants had 5.7 visits (SD = 1.7) between frailty and PFT measurements.

Effect Modi cation
Inconclusive results were found when exploring age, HIV status, or smoking modi cation of frailty on DL CO and FEV 1 (Supplemental Tables 4-11) and age modi cation of grip strength on FEV 1 (Supplemental Table 12).Therefore, primary results were presented without these interactions.
Neither age, HIV, nor smoking modi ed associations between gait speed or grip strength and DL CO (Supplemental Tables 13-18) or between gait speed and FEV 1 (Supplemental Tables 19-21).Neither HIV nor smoking modi ed the association between grip strength and FEV 1 (Supplemental Tables 22-23- 20).

Exploratory Analysis
In exploratory analyses, we examined associations of other frailty components (unintentional weight loss, exhaustion, and low physical activity) with subsequent impaired pulmonary function.Participants reporting low physical activity had higher odds of DL CO and FEV 1 impairment compared to participants not reporting low physical activity (OR = 1.76 [95% CI 1.32, 2.34]; p < 0.01, OR = 1.66 [95% CI 1.07, 2.57]; p = 0.02, respectively, Fig. 3).Unintentional weight loss and exhaustion were not signi cantly associated with subsequent pulmonary function (Fig. 3).

Discussion
We examined the associations between frailty and frailty components with subsequent pulmonary function in a large study of men with and without HIV, across a range of pulmonary function.Frailty, decreased grip strength, and low physical activity were signi cantly associated with increased odds of having impaired DL CO and FEV 1 , and slow gait speed was associated with impaired DL CO .Our results expand on the literature by showing associations between frailty and subsequent pulmonary function across multiple measures.Surprisingly, associations between frailty, gait speed, and grip strength with DL CO and FEV 1 were generally similar regardless of age, HIV serostatus, and smoking history.
Considering this and our previous study [18], we propose a bidirectional association between pulmonary function and physical function impairment or frailty, as has been suggested in the general population [14].Interventions that target components of both COPD and frailty may be the most effective in preventing decline in both conditions.
We did not nd differences in associations between physical function or frailty and pulmonary function by HIV serostatus or age.We did observe a higher non-signi cant percentage of PAWH with impaired DL CO compared to men without HIV (36% vs 31%, chi-square p-value = 0.09), and PAWH also had a slightly higher non-signi cant percentage of frailty (10.3% vs 9.4%, chi-square p-value = 0.32

Con ict of Interest:
The authors have no con ict of interest to declare for this speci c study. Funding: MA was supported by the Integrative Physiology of Aging Training Grant T32 AG000279-18.TTB was supported in part by K24 AI120834.KME was supported in part by K24 AG082527.This material is also the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Medical Center, Minneapolis, USA and Veterans Affairs Puget Sound, Seattle, USA.

Table 1 Baseline
Characteristics of the Cohort (DLCO and FEV1).DL CO models adjusted for Age, Cohort of enrollment, Center of enrollment, Race, HIV serostatus, and Cumulative pack-years of smoking ** FEV 1 models adjusted for Age, Cohort of enrollment, Center of enrollment, Race, HIV serostatus, and Cumulative pack-years of smoking and Framingham hard coronary 10-year risk score Gait Speed Models: *DL CO models adjusted for Age, Cohort of enrollment, Center of enrollment, Race, HIV serostatus, and Cumulative pack-years of smoking and Framingham hard coronary 10-year risk score.**FEV 1 models adjusted for Age, Cohort of enrollment, Center of enrollment, Race, HIV serostatus, and Cumulative pack-years of smoking, Framingham hard coronary 10-year risk score, education, diabetes status, high cholesterol, treatment for depression, and cocaine use.
).The lack of modi cation by HIV serostatus could result from the majority of the PAWH included in this analysis having limited disease progression with 86% having viral load ≤ 200 copies/ml and 74% having a CD4 + count over 500.Lack of modi cation by age could be due to one-time pulmonary function testing or the relatively narrow age range.This study has several strengths.It is a multicenter study with a large sample size including men with and without HIV.We used well-validated objective physical function measures of gait speed and grip strength and lung function.The extensive demographic and health-related data allowed us to adjust for numerous covariates.This study also has limitations.Although the MACS has more recently combined with the Women's Interagency HIV Study (comparable data not yet available in WIHS), this study only included U.S. men, > 90% of whom were White or Black, and study results may not be generalizable to women, other racial/ethnic groups, or non-U.S.populations.We only looked at single measurements for both physical function/frailty and pulmonary function (at different time points); so, could not examine changes over time.Participants with impaired pulmonary function at the 3-year follow-up may have had baseline impairments as well.Future studies are needed to determine temporality and con rm bidirectionality.by the Integrative Physiology of Aging Training Grant T32 AG000279-18.TTB was supported in part by K24 AI120834.KME was supported in part by K24 AG082527.This material is also the result of work supported with resources and the use of facilities at the Minneapolis Veterans Affairs Medical Center, Minneapolis, USA and Veterans Affairs Puget Sound, Seattle, USA.
In conclusion, among men with and without HIV, we found a strong association between frailty and impaired physical function with subsequent pulmonary function impairment.Combined with our prior analyses, these fundings support a bidirectional association between pulmonary function with physical function and frailty[18].A better understanding of mechanistic pathways underlying both frailty and pulmonary functions are needed to develop improved treatments to reduce declines in physical and pulmonary function and improve overall quality of life.DeclarationsFunding MA was supported